Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, Cardiovascular disease, Myocardium, TNF-alpha inhibitors, ESCAPE, Co-morbidities, RHYTHM
Brief summary
For aim 1, the proposed studies will be performed in 150 patients with RA and 25 subjects without RA (healthy volunteers) who will function as controls. For aim 2, 25 of the patients enrolled in aim 1 (who are in need for further treatment due to increased RA activity despite their current treatment) will be recruited to continue in the study for an additional 24 (+/- 2) weeks (or 6 months). These patient will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care. The investigators hypothesize that anti-TNF agents in RA patients without heart disease will not adversely affect the heart (will not cause a detrimental change in heart structure or its function).
Detailed description
Patients with Rheumatoid Arthritis (RA) have a shortened life expectancy compared to the general population. Cardiovascular disease (CVD), including heart failure (HF), is the primary cause of the extra deaths in RA. HF, in general, results from failure of the heart muscle to pump adequately. In other words the heart muscle in HF becomes weak. In patients without RA, the heart muscle gets larger before symptoms of HF appear. Contrary to that, patients with RA have reduced heart size and reduced heart strength. This may mean that in RA the pathway to heart failure may be different compared to what happens in patients without RA. It is possible - for example - that in RA the heart muscle becomes smaller before it becomes weak (while in non-RA patients the heart muscle becomes larger before it becomes weak). It is possible that cells that create inflammation in the joints may also do the same in the heart muscle making it smaller, thinner and eventually weaker. Patients with RA nowadays can be treated with a variety of medications for their joint inflammation. These medications are powerful and have reduced the risk of permanent joint damage and disability. However it is unknown what is the effect of these medications on the heart size and strength and whether they increase or decrease the risk for cardiovascular disease and heart failure. Among the medications used for RA are medications called TNF inhibitors. They are usually prescribed to patients who have joint inflammation that has not responded to treatment with the first line medication Methotrexate. Data in non-RA patients with advanced heart failure suggest that anti-TNF agents may not help heart failure and may even be harmful. However, the effect of these agents on the hearts of RA patients has never been directly studied. Some observational studies suggest that RA patients treated with TNF inhibitors have a lower risk of developing heart disease. Overall the knowledge regarding the effect of TNF inhibitors on RA patients heart function is limited.
Interventions
DRUGTNF inhibitors
TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment (usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the standard of care management of RA. The possible TNF inhibitors are: Remicade, Humira, Enbrel, Cimzia, Simponi.
DRUGDMARDs
Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
For RA patients (150 patients): INCLUSION CRITERIA * Diagnosis of Rheumatoid Arthritis by 2010 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) diagnostic criteria * Age\>18 years old * Moderate to high RA disease activity defined by a Clinical Disease Activity Index (CDAI) of \>10 * Stable dose of Methotrexate for 6 weeks prior to enrollment * Stable doses of Nonsteroidal anti-inflammatory drug (NSAID) and prednisone (if already taking these medications) for 2 weeks prior to study
Exclusion criteria
* Prior self reported or physician diagnosed CV event (MI; angina; stroke or Transient Ischemic Attach (TIA); Heart Failure (HF); prior CV procedure (e.g., coronary artery bypass graft, angioplasty, valve replacement, pacemaker) * Contraindications to having a PET-CT scan or receive adenosine or Fludeoxyglucose (FDG) * Active treatment for Cancer * Uncontrolled hypertension * Diabetes * Smoking * Treatment with a TNF inhibitor or other biologic currently or within the last 6 months * Current treatment with Triple Therapy or within the last 2 months * Untreated positive purified protein derivative (PPD) tuberculosis skin test or active tuberculosis * History of Lymphoma and Melanoma * Ejection Fraction (EF) \< 40% (if not known in advance then the Study Visit I Echocardiogram results will be used to exclude the patient from randomization and follow up) * Change in NSAID/Prednisone dosage in last 2 weeks * Participation in other research studies involving imaging/radiation exposure For non-RA subjects (25 controls): INCLUSION CRITERIA * Age\>18 years old * Absence of diagnosis of RA
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Myocardial FDG Uptake | Baseline | This is designed to evaluate the baseline characteristics of the cross sectional RA cohort to understand the correlation of disease activity measured by the Clinical Disease Activity Index (CDAI) with myocardial inflammation measured by fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) scan at the baseline visit. Myocardial FDG uptake is classified as diffuse or focal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Baseline, 6-Month Follow-up | This is designed to measure the myocardial inflammation, and its association with change in CDAI, after ramp-up of RA therapy over 6 months. Measurements are taken at baseline and 6-months post treatment escalation. Myocardial FDG uptake is classified as diffuse or focal. |
| LV Structure (Mean EDVI) in Association With Myocardial FDG Uptake | Baseline | This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) structure measured by 2D/3D echocardiogram at the baseline visit. |
| LV Function (Mean Stroke Volume Index) in Association With Myocardial FDG Uptake | Baseline | This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) function measured by 2D/3D echocardiogram at the baseline visit. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients - DMARDs + TNF Inhibitors Patients will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care.
TNF inhibitors: TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment (usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the standard of care management of RA.
The possible TNF inhibitors are: Remicade, Humira, Enbrel, Cimzia, Simponi.
DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs. | 8 |
| Patients - DMARDs Only Patients will receive their current treatment in an open label protocol in the context of standard of care.
DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs. | 4 |
| Healthy Volunteers Subjects without RA who will function as controls. | 16 |
| Patients - Cross Sectional (RA) A cohort of patients with Rheumatoid Arthritis will undergo the baseline study visit only (no randomization to treatment). Note, that those who were randomized, their data will be utilized in the full cross sectional analysis. | 121 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Non-Compliance | 0 | 0 | 0 | 3 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Patients - DMARDs + TNF Inhibitors | Patients - DMARDs Only | Healthy Volunteers | Patients - Cross Sectional (RA) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 1 Participants | 16 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 2 Participants | 15 Participants | 105 Participants | 130 Participants |
| Age, Continuous | 55.125 years | 56 years | 52 years | 55.6 years | 54.38 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants | 52 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 12 Participants | 69 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 5 Participants | 28 Participants | 36 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 36 Participants | 36 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 3 Participants | 11 Participants | 53 Participants | 72 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 12 Participants | 105 Participants | 127 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 4 Participants | 16 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 4 | 0 / 16 | 0 / 121 |
| other Total, other adverse events | 1 / 8 | 0 / 4 | 0 / 16 | 6 / 121 |
| serious Total, serious adverse events | 1 / 8 | 0 / 4 | 0 / 16 | 0 / 121 |
Outcome results
Primary
Number of Participants With Myocardial FDG Uptake
This is designed to evaluate the baseline characteristics of the cross sectional RA cohort to understand the correlation of disease activity measured by the Clinical Disease Activity Index (CDAI) with myocardial inflammation measured by fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) scan at the baseline visit. Myocardial FDG uptake is classified as diffuse or focal.
Time frame: Baseline
Population: 2 RA patients and 1 healthy volunteer (control subject) were not included in this analysis population because the subjects withdrew study participation prior to scan (no data were collected).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Patients - Cross Sectional (RA) | Number of Participants With Myocardial FDG Uptake | Diffuse FDG Uptake | 21 Participants |
| Patients - Cross Sectional (RA) | Number of Participants With Myocardial FDG Uptake | Focal FDG Uptake | 25 Participants |
| Patients - Cross Sectional (RA) | Number of Participants With Myocardial FDG Uptake | No FDG Uptake | 73 Participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake | Diffuse FDG Uptake | 4 Participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake | Focal FDG Uptake | 1 Participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake | No FDG Uptake | 10 Participants |
Secondary
LV Function (Mean Stroke Volume Index) in Association With Myocardial FDG Uptake
This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) function measured by 2D/3D echocardiogram at the baseline visit.
Time frame: Baseline
Population: Only 119 out of 121 subjects had data analyzed due to 2 subject withdrawals prior to scan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients - Cross Sectional (RA) | LV Function (Mean Stroke Volume Index) in Association With Myocardial FDG Uptake | 58.6 ml/m^2 | Standard Deviation 13.9 |
| Healthy Volunteers | LV Function (Mean Stroke Volume Index) in Association With Myocardial FDG Uptake | 31.3 ml/m^2 | Standard Deviation 7.5 |
Secondary
LV Structure (Mean EDVI) in Association With Myocardial FDG Uptake
This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) structure measured by 2D/3D echocardiogram at the baseline visit.
Time frame: Baseline
Population: Only 119 out of 121 subjects had data analyzed due to 2 subject withdrawals prior to scan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients - Cross Sectional (RA) | LV Structure (Mean EDVI) in Association With Myocardial FDG Uptake | 53.8 ml/m^2 | Standard Deviation 11 |
| Healthy Volunteers | LV Structure (Mean EDVI) in Association With Myocardial FDG Uptake | 49.1 ml/m^2 | Standard Deviation 12.9 |
Secondary
Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy
This is designed to measure the myocardial inflammation, and its association with change in CDAI, after ramp-up of RA therapy over 6 months. Measurements are taken at baseline and 6-months post treatment escalation. Myocardial FDG uptake is classified as diffuse or focal.
Time frame: Baseline, 6-Month Follow-up
Population: 2 TNFi, and 2 DMARDs and 1 healthy volunteer (control subject) were not included in this analysis population because the subjects withdrew participation prior to study completion or scan (no data were collected).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients - Cross Sectional (RA) | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Focal Baseline FDG Uptake | 1 participants |
| Patients - Cross Sectional (RA) | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Focal Follow-up FDG Uptake | 1 participants |
| Patients - Cross Sectional (RA) | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Diffuse Baseline FDG Uptake | 4 participants |
| Patients - Cross Sectional (RA) | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Diffuse Follow-up FDG Uptake | 2 participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Diffuse Follow-up FDG Uptake | 0 participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Focal Baseline FDG Uptake | 1 participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Diffuse Baseline FDG Uptake | 1 participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Focal Follow-up FDG Uptake | 0 participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Diffuse Follow-up FDG Uptake | NA participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Focal Follow-up FDG Uptake | NA participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Diffuse Baseline FDG Uptake | 4 participants |
| Healthy Volunteers | Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy | Focal Baseline FDG Uptake | 1 participants |